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Scientists identify 'finger' that triggers tumor suppression

By Mark Shwartz

Or Gozani

In recent years, scientists have discovered five closely related proteins—known as Inhibitor of Growth (ING) tumor suppressors—that play a significant role in certain cancers and cellular aging. Because of their ability to suppress cancerous cells, these proteins, called ING1 through ING5, have been the focus of intense research.

Now scientists from Stanford, the University of Colorado-Denver and other institutions have determined how one of the tumor suppressors, ING2, is able to promote protective cellular responses against injured DNA. This finding, which may lead to new diagnostic markers and more efficacious cancer treatments with fewer side effects, was reported in two studies published in the May 21 advance online edition of the journal Nature.

Protein 'finger'

The studies were led by Or Gozani, assistant professor of biological sciences at Stanford, and Tatiana Kutateladze of the University of Colorado-Denver Department of Pharmacology.

In one paper, Gozani and his colleagues solved a longstanding question about how the ING2 protein responds when a DNA molecule is damaged. The answer involves the way DNA in our cells is packaged. "If you stretch out a strand of human DNA, it would be about 6 feet long," Gozani said. "To fit inside a tiny cell, therefore, the DNA is condensed and wrapped around proteins called histones."

Each spherical histone molecule has a tail that is sometimes tagged with molecules of methyl (CH3)—a reversible process known as methylation, which can alter DNA activity. Gozani and his coworkers discovered that damaged DNA sends out a signal to ING2, which then looks for histones with three methyl molecules attached at specific sites on their tails. ING2 then swoops in and, using a specialized molecular structure dubbed the "plant homeodomain [PHD] finger," binds to the trimethylated histone—an act that shuts down dangerous genes on the DNA molecule and thus prevents production of harmful proteins that could eventually lead to tumor formation.

"In response to acute cellular stresses, such as DNA damage, you want to shut off actively transcribed genes that produce proteins that facilitate cell division," Gozani said. "If you don't, cells harboring mutated DNA can be propagated, and these mutated cells are far more likely than normal cells to become cancerous. ING2 functions in tumor suppression by shutting off these genes until the damaged DNA is repaired, and the cell is safe once again to divide."

In normal cells, ING2 is believed to inhibit the formation and growth of cancerous tumors, such as melanoma and breast cancer. However, if ING function is disrupted, cancers can occur.

Novel treatments

In the second paper, the Kutateladze lab and colleagues presented a high-resolution, three-dimensional image of an ING2 PHD finger bound to a trimethylated histone. "There are more than 150 human proteins that have a PHD finger, and malfunction of many of these are implicated in the development of diverse disorders," Gozani said. "Knowledge of this structure should provide insight into how to develop novel drugs to target ING2-sensitive cancers and a wide range of other human diseases."

Twenty-three researchers contributed to one or both Nature papers, including Katrin Chua, assistant professor of medicine at Stanford and at the Veterans Affairs Palo Alto Health Care System; Stanford postdoctoral scholars Xiaobing Shi (lead author), Tao Hong and Eriko Michishita; life sciences research associate Kay Walter; former technician Mark Ewalt; and Stanford undergraduates Tiffany Hung and Dylan Carney. Other co-authors came from Harvard Medical School, University of Utah, Laval University Cancer Research Center (Quebec) and Albert Einstein College of Medicine.

Funding was provided by the National Institutes of Health, Burroughs Wellcome Fund, U.S. Department of Energy, American Heart Association, University of Colorado Cancer Center and American Cancer Society.